Cystic fibrosis (CF) is a genetic disease affecting exocrine organs including the lungs and leading, in most patients, to chronic pulmonary infections with Pseudomonas aeruginosa. Analyses of the infectious disease aspects of this condition have suggested that these patients suffer from a local defect in mucosal Pseudomonas-specific immunity affecting delayed-type hypersensitivity in the lungs. Since the reported immunologic abnormalities in CF begin when the affected children are only a few years of age there is reason to believe that developmental aspects of cell-mediated immunity are impaired or that the condition indeed represents a congenital immunologic defect. Our preliminary studies in this area have confirmed earlier findings that CF blood T cells fail to respond to Pseudomonas antigens in vitro and we have formulated a series of hypotheses that could account for this deficiency. Immunobiological approaches to the study of immunocompetent cells, including T lumphocytes and macrophages, are aimed at the following possibilities: (1) anti-Pseudomonas T cell clones are sequestered in the lungs and therefore go undetected in assays of blood T cell reactivity, (2) pulmonary T cells are not activated by Pseudomonas antigens because antigen-presenting cells in the lungs and blood fail to present the antigens, or (3) conditions arising in CF abrogate successful T cell activation by modulating la antigen-dependent cellular interactions. These hypotheses will be tested largely by lymphocyte culture techniques designed to study interactions between T cells and macrophages from various sources. In addition, bronchial fluids and soluble products from Pseudomonas organisms will be examined for their ability to interfere with immune T cell activation. It is the intent of this research to provide insight into the basic immunologic defect in CF that allows for recurrent pulmonary infections and to suggest new approaches to the immunologic management of CF.